Project Summary/Abstract: The opioid epidemic has resulted in a striking, nationwide increase in the number of drug-use related deaths and life-threatening medical complications. It has crossed sociodemographic lines, involving people from all income levels and age groups. Among the most serious of the medical complications has been the increase in injection drug use (IDU)-related infections including HIV, hepatitis and invasive bacterial infections. As in the past, Staphylococcus aureus (SA) accounts for the majority of these infections. Treatment of SA infections in IDU remains challenging. There have been few recent investigations that have examined the epidemiology and molecular characteristics of SA in IDU. There is a critical gap in knowledge regarding the resurgence of these infections. New York City (NYC) is among the areas most affected by the opioid epidemic. A marked increase in the number of invasive community-based SA infections, especially endocarditis has been noted. This proposal will prospectively characterize persons with bacteremic IDU-related SA infections and their isolates across NYC. We hypothesize that the resurgence of SA infections among IDUs: 1) includes distinct IDU populations with patterns of drug use that differ from those in the past; 2) is associated with, unexplored transmission pathways; 3) has geographic hotspots related to IDU; 4) is associated with the emergence/reemergence of clones adapted to the drug use environment; and 5) may result in these SA strains spreading into the non-IDU population. Our aims are: 1) To determine risk factors for community-associated SA bacteremia in IDU compared to non-IDU, in a prospective cohort across NYC hospitals. A citywide database comparing sociodemographic, clinical and geospatial data from subjects with and without IDU-related SA bacteremias from healthcare facilities across NYC will be established. The analysis will identify risks for SA infections among IDUs, create a prediction model to more readily identify IDUs and develop prevention strategies for this group. 2) To compare the population structure of IDU and non-IDU SA bacteremic isolates. A maximum likelihood phylogenetic tree will be constructed and used to help establish relationships among strains and detect potential drug use networks. These will also be examined by Bayesian methods to reconstruct possible transmission networks. WGS will also identify virulence genes that contribute to the success of the dominant SA-IDU clones. These studies, performed with NYC Infectious Diseases physicians and the NYC Department of Health will be important in laying the groundwork for identifying specific IDU-related risks for infections and developing targeted interventions aimed at decreasing the number of infection-related complications of IDU.